Recommendations for the timing, dosage, and usage of corticosteroids during cytokine release syndrome (CRS) caused by chimeric antigen receptor (CAR)-T cell therapy for hematologic malignancies

Clinical question What are the recommendations for the timing, dosage, and usage of corticosteroids during cytokine release syndrome (CRS) caused by chimeric antigen receptor (CAR)-T cell therapy for hematologic malignancies? Recommendations The administration of corticosteroids in CRS should be managed depending on the risk stratification and grading of CRS occurrence, combined with clinical situation, dynamic assessments of CAR-T cell kinetics and cytokine level changes [Table 1]. Table 1 - Recommendations for the management of CRS with corticosteroids in the patients receiving CAR-T therapy. CRS Grades Standard-risk patients High-risk patients Grade 1 Administration of corticosteroids is not recommended. Dexamethasone 5–10 mg for one dose for persistent fever lasting after interventions including antipyretics, IL-6 receptor /IL-6 antagonists, or hydration.The corticosteroid administration should be repeated If there is no improvement within 24 hours. Grade 2 Dexamethasone 5–10 mg for one dose in combination with IL-6 receptor/IL-6 antagonists. Reassess every 12 hours and repeat dexamethasone 10 mg for one dose if if there is no improvement. Dexamethasone 10 mg for one dose simultaneously with IL-6 receptor/IL-6 antagonists. Reassess every 6 hours and repeat dexamethasone 10 mg for one dose if there is no improvement. Grade 3 Administer dexamethasone 10 mg i.v. every 6 hours. If there is no improvement within 24 hours, increase dexamethasone to 20 mg i.v. every 6 hours for 1–3 days. Once CRS improves to Grade 1 or less, taper and/or stop corticosteroids depending on clinical situation. If refractory, manage as Grade 4. Administer dexamethasone 10–20 mg iv every 6 hours for 1–3 days and reassess every 24 hours. Once CRS improves to Grade 1 or less, taper and/or stop corticosteroids depending on clinical situation. If refractory, manage as Grade 4. Grade 4 Administer methylprednisolone 500 mg twice daily for three days, then reduce the dose by half every two days until reaching 60 mg of methylprednisolone or reduce the dose depending on the clinical situation. The same as Standard-risk patients High-risk patients: Defined as those with a high tumor burden, high-dose CAR-T cell infusion, use of CAR-T cells costimulated with CD28, acute leukemia, a high comorbidity index, an older age, and high baseline inflammation levels prior to infusion. Standard-risk patients: Defined as those who are not classified as high risk. Dexamethasone can be replaced with an equal amount of methylprednisolone (Evidence quality level: Moderate, Strong recommendation). CRS: Cytokine release syndrome. For low-grade CRS (Grades 1–2), it is recommended that high-risk patients use low doses of corticosteroids early on; standard-risk patients should delay the timing and reduce the dosage of corticosteroid use as much as possible. For high-grade CRS (Grades 3–4), both high-risk and standard-risk patients should be actively managed with corticosteroids. Grading Criteria for the Quality of Evidence and Strength of Recommendations Currently, there is no high-level evidence from clinical studies on the timing and dosage of corticosteroids in CRS. Only a few prospective cohort studies and retrospective studies have explored the effects of corticosteroids on the prevention and treatment of CRS, and these investigations have yielded seemingly contradictory conclusions. In the ZUMA-1 study, cohorts 4 and 6 supported the prophylactic and early use of corticosteroids, as this approach reduced the cumulative dose of corticosteroids, did not affect the complete response (CR) rate or survival from CAR-T cell therapy, and decreased the incidence of severe CRS.[1,2] However, the limitation of this study is that it focused only on Axi-Cel treatment for lymphoma with CD28 as a costimulatory domain, which may not be generalizable to other types of tumors or CAR-T cells. In another study conducted by MD Anderson, a retrospective analysis of 100 patients treated with Axi-Cel at a single center explored the impact of corticosteroids on clinical outcomes in patients with relapsed or refractory large B-cell lymphoma receiving standard CD19 CAR-T cell therapy.[3] Although the study indicated that the dosage, duration, and timing of corticosteroid treatment did not affect CAR-T cell expansion, further research is needed to assess the impact of these factors on the cytotoxic activity of CAR-T cells and on cytokine production and trafficking. Until we understand the underlying mechanisms, cautious use of corticosteroids, with a focus on delaying their initiation and limiting their cumulative dose and duration depending on the clinical situation, might be prudent. It was concluded from this study that early or high-dose use of corticosteroids, although not affecting relapse rates or progression-free survival (PFS), shortened overall survival (OS) and increased the risk of nonrelapse mortality; hence, the lowest possible dose and the shortest course of treatment for CRS, and the initiation of corticosteroid use should be delayed if clinically feasible. In 2014, an early study using CAR-T cell therapy for B cell acute lymphoblastic leukemia (B-ALL) showed that the lympholytic effect of steroids not only affected the in vivo expansion of infused CAR-T cells but also impacted the clinical outcomes of patients with severe CRS.[4] Despite achieving a complete response (CR), all three patients with B-ALL who received high-dose steroid treatment relapsed, whereas those who were untreated or who received only tocilizumab did not show evidence of disease relapse after achieving CR. These results strongly suggest that tocilizumab should be the first-line treatment for severe CRS, with high-dose corticosteroids reserved only for life-threatening CRS patients unresponsive to tocilizumab. Evidence Summary In 2021, Dan Chen et al[5] conducted a retrospective study to observe 67 patients with low-dose dexamethasone in preventing CRS following CD19 CAR-T cell therapy in ALL. The control group including Grade 1–2 CRS did not receive steroid prophylaxis. In the prophylactic group, Grade 1–2 CRS received a single dose of 2.5 mg intravenous dexamethasone, with a cumulative dose ≤5 mg/d; and Grade 3–4 CRS received intravenous dexamethasone (20–40 mg/d). The incidence of Grade 1–2 CRS in the prophylactic group was 91.7% versus 61.3% in the control group, and the incidence of Grade ≥3 CRS was 8.3% versus 38.7%. The study proved that early use of low-dose dexamethasone reduces the incidence of severe CRS during CAR-T cell therapy in patients with ALL, and does not affect leukemia remission rates or increase the risk of infection. The detailed summary of each article[1–5] and the recommendations from National and International Guidelines are shown in Supplementary File, https://links.lww.com/CM9/C218. Funding This work was supported by grants from the National Natural Science Foundation of China (Nos. 82270233, 81830004 and 82070168), National Natural Science Foundation of China Youth Science Foundation Project (No. 82200246), Translational Research Grant of NCRCH (No. 2020ZKZC04), National Key R&D Program of China (No. 2021YFA1100800) and Shanghai Municipal Health Commission (No. 2020CXJQ02). Conflicts of interest None.